Eligibility criteria
Studies will be selected for review according to the eligibility criteria below.
Study design and participants
This review will include randomised control trials, observational cohort, cross-sectional and case-control studies reporting original response rate data in adult human participants. Eligible studies will be grouped together to calculate response rates, rather than treating the studies separately.
Participants will be patients with biopsy-proven oesophageal, or gastro-oesophageal junction adenocarcinoma (confirmed by histopathologist), who have been treated with neo-adjuvant chemotherapy or chemo-radiotherapy prior to surgical resection and had an interim PET/CT examination (after one-cycle of neo-adjuvant therapy) and a PET/CT after completion of neo-adjuvant therapy. Recurrent oesophageal adenocarcinoma will not be included. Studies of patients with histology other than adenocarcinoma and those who did not have an interim or completion PET/CT examinations will be excluded. Studies with mixed patient cohorts will also be excluded.
PET/CT examinations
The radioisotope 18-Fluorine (18F) FDG must have been used for the PET/CT examinations. Studies using other radioisotopes will be excluded but if the article contains FDG data, attempt will be made to extract these data alone. The maximum standardised uptake value (SUVmax) must have been measured by an appropriately trained and experienced professional. SUVmax is defined as the voxel with the highest SUV value in a defined region of interest [15].
Treatment response
The threshold for response classification, defined in terms of the percentage reduction in SUVmax, must be stated. The reference standard will be the pathological tumour regression grade (TRG), defined by validated pathological classification systems Mandard [16] or Becker [17]. Occasionally, patients will progress during neo-adjuvant therapy and no longer be suitable for surgery. Attempt will be made to capture these data also.
Searches
Electronic Searches
A comprehensive search strategy using text words and controlled vocabulary has been designed using MEDLINE (OVID). (Table 1)
Table 1. Search terms and strategy
#
|
Searches
|
1
|
Esophageal Neoplasms/
|
2
|
((oesophag* or esophag*) adj (neoplas* or adenocarcinoma or tumo?r*)).tw.
|
3
|
1 or 2
|
4
|
exp Adenocarcinoma/
|
5
|
(oesophag* or esophag*).tw.
|
6
|
4 and 5
|
7
|
3 or 6
|
8
|
Positron Emission Tomography Computed Tomography/
|
9
|
(PET-CT or PET CT).tw.
|
10
|
((early or interim or ad interim or endpoint or timepoint) adj2 (PET or FDG-PET)).tw.
|
11
|
Positron-Emission Tomography/
|
12
|
(PET or FDG-PET or 18-FDG).tw.
|
13
|
Fluorodeoxyglucose F18/
|
14
|
or/8-13
|
15
|
7 and 14
|
16
|
exp Treatment Outcome/
|
17
|
exp "Predictive Value of Tests"/
|
18
|
exp "sensitivity and specificity"/
|
19
|
exp Disease-Free Survival/
|
20
|
exp Prognosis/
|
21
|
(sensitivity or specificity).tw.
|
22
|
((treatment or therapeutic) adj1 (response or outcome*)).tw.
|
23
|
(predict* or prognos*).tw.
|
24
|
((tumo?r or metabolic) adj2 response).tw.
|
25
|
tumo?r glucose.tw.
|
26
|
(glucose adj (standard uptake or SUV)).tw.
|
27
|
Glucose/
|
28
|
or/16-27
|
29
|
15 and 28
|
30
|
limit 29 to (english language and yr="2005 -Current")
|
31
|
randomized controlled trial.pt.
|
32
|
controlled clinical trial.pt.
|
33
|
randomized.ab.
|
34
|
placebo.ab.
|
35
|
drug therapy.fs.
|
36
|
randomly.ab.
|
37
|
trial.ab.
|
38
|
groups.ab.
|
39
|
or/31-38
|
40
|
exp animals/ not humans.sh.
|
41
|
39 not 40
|
42
|
epidemiologic studies/
|
43
|
exp case control studies/
|
44
|
exp cohort studies/
|
45
|
Case control.tw.
|
46
|
exp Longitudinal Studies/
|
47
|
exp Retrospective Studies/
|
48
|
exp Prospective Studies/
|
49
|
(cohort adj (study or analys* or studies)).tw.
|
50
|
exp Follow-Up Studies/
|
51
|
(Follow up adj (study or studies)).tw.
|
52
|
exp Cross-Sectional Studies/
|
53
|
(observational adj (study or studies)).tw.
|
54
|
(Longitudinal or Retrospective or Cross sectional).tw.
|
55
|
or/42-54
|
56
|
41 or 55
|
57
|
- and 56
|
This strategy will be translated and run in the following electronic databases: MEDLINE [OVID], Embase [OVID], Cochrane Library [Wiley], Cumulative Index of Nursing and Allied Health Literature (CINAHL) [EBSCO], Scopus [Elsevier], Web of Science [Thomson Reuter], International Clinical Trials Registry Platform (ICTRP) Search Portal [World Health Organisation] and ClinicalTrials.gov.
The search will be limited to articles published in English from 2005 onwards, because 3D PET became integrated into most PET/CT scanners providing more standardisation in SUVmax from this timepoint onwards [13]. Study filters for randomised control trials and observational study types will be applied. Reference lists of all eligible studies will be checked and undergo citation tracking for additional eligible studies.
Selection process
Following the systematic search described above, all titles and abstracts will be screened by two independent authors against the defined eligibility criteria. Full text articles will be obtained for all studies that meet the criteria. In cases of disagreement following screening of titles and abstracts, a third author will be asked to review and decide upon the suitability of the study. Reasons for exclusion will be recorded. A flowchart will be used to summarise the numbers of included and excluded studies at each stage of the selection process.
Data management and extraction process
The results of the screening process will be shared between the reviewers using an output file that can be imported into Mendeley Desktop 1.19.4. Authors will be instructed to create a new library to keep the screened studies separate. The full-text articles will be included in the output file. Duplicate items will be identified and one of the copies deleted.
Relevant data will be extracted from the final set of eligible articles. Data will be inputted into a Microsoft Excel 365 spreadsheet designed specifically for this review (additional file 2 - SystRev_DataItems). Two independent authors will extract the relevant data from the articles. In cases of disagreement, a third author will be asked to review the article and decide upon the data to be recorded. Articles reporting findings from duplicate sets of patients will be combined and extracted as a single study.
Data items
- Patient characteristics; number of patients included, age, gender, tumour location, neo-adjuvant regimen, pathological response rate at surgery, length of survival.
- Study characteristics; primary author, publication year, study dates, country of study, study design, number of centres, length of time between interim PET and surgery, length of time between interim PET and surgery, conclusions of study.
- PET/CT characteristics; timing of interim PET/CT (days after treatment inception), type of scanner and acquisition (including PET reconstruction method), length of fasting before injection, time between FDG injection and PET, PET quantification method, interpreter(s), threshold criteria for defining response, proportion of patients with early response, proportion of patients with response after completion of neo-adjuvant therapy.
Outcomes
The primary outcome of the systematic review will be the response rate based on SUVmax following early PET/CT after one cycle of neo-adjuvant therapy. The secondary outcomes will be the response rate following PET/CT after completion of neo-adjuvant therapy and the diagnostic accuracy of PET/CT both early and after completion of neo-adjuvant therapy. Diagnostic accuracy will be defined by calculating sensitivity and specificity, using the reference standard of pathological tumour regression grade. For diagnostic accuracy, responders will be classified at pathology as having a Mandard TRG 1–3 or Becker TRG 1–2 and non-responders as Mandard TRG 4–5 or Becker TRG 3.
Quality assessment and risk of bias
The methodological quality of eligible studies will be assessed using the Quality Assessment of Studies of Diagnostic Accuracy Included in Systematic Reviews (QUADAS–2) criteria [18], which comprises four domains, each assessing the risk of bias and clinical application. Perceived quality will be graded low, high or unclear risk. The question “were uninterpretable and/or intermediate test results reported?” has been added to the QUADAS–2 checklist. (additional file 3—QUADAS–2)
Data synthesis
If the studies are sufficiently homogenous in their design, outcome assessment and follow-up, we will conduct a meta-analysis using a random effects model (DerSimonian and Laird [19]) using the current version of R (R Foundation for statistical computing, Vienna, Austria) [20]. We will combine the percentage of patients with early and completion treatment response in each individual study to estimate a pooled prevalence with a 95% confidence interval (CI). Sensitivities and specificities of FDG PET in individual studies will also be calculated for early and completion PET/CT examinations, and subjected to meta-analysis, if feasible. The results of the individual studies will be displayed with a receiver operator curve (ROC) curve, and a weighted symmetric summary ROC (sROC) curve with a 95% CI will be computed [21]. We will also pool survival data for metabolic responders and non-responders obtaining a median survival time in each group with a 95% CI. We will assess heterogeneity between specific study estimates using the inconsistency index (I2 statistic [22]). If heterogeneity is considerable (I2 > 75%) and the p value <0.1, quantitative data synthesis will not be performed [14]. We will investigate sources of heterogeneity between studies using subgroup analyses by stratifying original co-variates according to methodological quality (QUADAS–2 score), sample size, PET injection time, neo-adjuvant therapy regimen, number of cycles of neo-adjuvant therapy and histopathological response.